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Absence of the OPTN mutation in a patient with ALS and familial primary open angle glaucoma
Journal of the Neurological Sciences 309 (2011) 16–17
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Absence of the OPTN mutation in a patient with ALS and familial primary open angle glaucoma P. Corcia a, b,⁎, J. Praline a, b, A.M. Guennoc a, R.A. Thépault b, P.H. Gordon d, H. Blasco b, c, C.R. Andres b, c, P. Vourc'h b, c a
Centre SLA, CHRU de Tours, Tours, France UMR INSERM U930, Université François Rabelais de Tours, Tours, France Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours, Tours, France d Centre de référence SLA, CHU Pitié-Salpétrière, Paris b c
a r t i c l e
i n f o
Article history: Received 2 March 2011 Received in revised form 25 July 2011 Accepted 26 July 2011 Available online 17 August 2011
a b s t r a c t The optineurin (OPTN) gene, known to be implicated in primary open-angle glaucoma (POAG), is the more recent genetic factor linked to ALS. We report the case of a 75 year-old man who developed ALS and whose medical history was dominated by a familial POAG. The absence of OPTN gene mutation in a patient who suffered from two conditions linked to mutations of this gene does not support involvement of OPTN in ALS. © 2011 Elsevier B.V. All rights reserved.
Keywords: ALS–POAG–OPTN gene
1. Introduction The number of genes identified in both familial and sporadic amyotrophic lateral sclerosis considerably increased during the last 5 years. The most recent genetic factor linked to ALS is the optineurin (OPTN) gene [1]. OPTN gene mutations are also known to be implicated in primary open-angle glaucoma (POAG) [2]. Maruyama and colleagues reported both homozygous and heterozygous mutations in OPTN in ALS patients without POAG in two Japanese families, and a homozygous mutation in a patient with both ALS and POAG [1]. Three recent studies on European and Japanese population of ALS patients without POAG did not support the contribution of OPTN in ALS [3–5]. Thus, the relationship between ALS and mutations in the OPTN gene remains controversial. We report the first case of a patient with both ALS and familial POAG without OPTN mutation. 2. Case report A 75 year-old man was first seen in October 2010 for a one-year history of progressive left lower limb weakness. His past medical history was dominated by familial POAG that involved also his father and one of his two brothers. There was no consanguinity within the family or neurological disorders.
Clinical examination showed motor weakness of grade 4 in the left leg, and grade 5 in the upper limbs. Atrophy was seen proximally in the lower limbs and in the hands. Tendon reflexes were hypoactive in the legs and brisk in the arms. Plantar responses were extensor with bilateral Hoffmann's signs. Fasciculations were profuse at the four limbs. There were no sensory, sphincter, oculomotor, cerebellar or extra pyramidal signs. The ALSFRS-R score was 42 out of 48. Nerve conduction studies were normal in all four limbs without conduction block. Electromyography disclosed denervation in four limbs, sparing the tongue. Spinal and cerebral MRI were both normal as was the spinal fluid analysis. Blood examination excluded all ALS mimicking syndromes. Riluzole was initiated in November 2010. Three months later, the ALSFRS-R score was graded 40 and clinical examination showed progression of the upper motor neuron and lower motor neuron signs. Owing to the presence of POAG in this family, the entire coding sequence of the OPTN gene and its proximal promoter was screened by bidirectional DNA sequencing analysis (ABI 3130xl; Applied Biosystems, Courtaboeuf, France) (primers available upon request). We observed no variation in the OPTN gene. We also excluded mutations in the coding sequences of SOD1, TARDBP and FUS genes. Our observation supports the weakness of the linkage between the OPTN gene and sporadic ALS. 3. Discussion
⁎ Corresponding author at: INSERM 930, Faculté de Médecine, 10, Boulevard Tonnellé, 37044 Tours CEDEX1, France. Tel.: + 33 247473724; fax: + 33 247473808. E-mail address: [email protected] (P. Corcia). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.044
Although the onset of ALS was at least 15 years later than those noted in ALS linked to OPTN gene mutations, we studied the gene for possible mutations because of association identified by other authors;
P. Corcia et al. / Journal of the Neurological Sciences 309 (2011) 16–17
OPTN mutations have been detected in familial POAG and ALS, an association that was strengthened by the discovery of a homozygous Q398X mutation in OPTN in a Japanese patient who developed ALS and POAG [1,2]. Marayuma and colleagues did not report whether the relatives of the patient who carried a heterozygous mutation Q398X in OPTN also suffered from POAG [1]. We did not detect a mutation in the entire coding sequence or the proximal promoter of the OPTN gene in our patient with ALS and familial POAG. Moreover, we were able to sequence the exon 5 of OPTN, indicating that the patient did not carry a homozygous deletion of this exon (Alu-mediated recombination) similar to the one reported by Marayuma and colleagues in two ALS patients from a single family [1]. The prevalence of mutations in the OPTN gene was estimated to be 17% in the familial POAG population [2]. Although it remains difficult to assess the frequency of OPTN mutation in ALS because of the small number of studies performed to date, it seems negligible (3/1379 sporadic ALS patients; 0.2%) [1,3,4]. Thus, mutations in the OPTN gene could be involved in a very small number of ALS cases. However, our observation, the first of a case of
17
ALS with familial POAG not showing a mutation of the OPTN gene, suggests that OPTN may not be implicated in the etiology of ALS. The co-occurrence of these two disorders, POAG and ALS, might be due to chance alone.
References [1] Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010;465:223–6. [2] Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;295:1077–9. [3] Belzil V, Daoud H, Desjarlais A, Bouchard JP, Dupré N, Camu W, et al. Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis. Neurobiol Aging 2011;32(3):555. [4] Iida A, Hosono N, Sano M, Kamei T, Oshima S, Torao Tokuda T, et al. Optineurin mutations in Japanese amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry (in press). [5] Millecamps S, Boillée S, Chabrol E, Camu W, Cazeneuve C, Salachas F, et al. Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 2011;32(3):557.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Absence of the OPTN mutation in a patient with ALS and familial primary open angle glaucoma P. Corcia a, b,⁎, J. Praline a, b, A.M. Guennoc a, R.A. Thépault b, P.H. Gordon d, H. Blasco b, c, C.R. Andres b, c, P. Vourc'h b, c a
Centre SLA, CHRU de Tours, Tours, France UMR INSERM U930, Université François Rabelais de Tours, Tours, France Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours, Tours, France d Centre de référence SLA, CHU Pitié-Salpétrière, Paris b c
a r t i c l e
i n f o
Article history: Received 2 March 2011 Received in revised form 25 July 2011 Accepted 26 July 2011 Available online 17 August 2011
a b s t r a c t The optineurin (OPTN) gene, known to be implicated in primary open-angle glaucoma (POAG), is the more recent genetic factor linked to ALS. We report the case of a 75 year-old man who developed ALS and whose medical history was dominated by a familial POAG. The absence of OPTN gene mutation in a patient who suffered from two conditions linked to mutations of this gene does not support involvement of OPTN in ALS. © 2011 Elsevier B.V. All rights reserved.
Keywords: ALS–POAG–OPTN gene
1. Introduction The number of genes identified in both familial and sporadic amyotrophic lateral sclerosis considerably increased during the last 5 years. The most recent genetic factor linked to ALS is the optineurin (OPTN) gene [1]. OPTN gene mutations are also known to be implicated in primary open-angle glaucoma (POAG) [2]. Maruyama and colleagues reported both homozygous and heterozygous mutations in OPTN in ALS patients without POAG in two Japanese families, and a homozygous mutation in a patient with both ALS and POAG [1]. Three recent studies on European and Japanese population of ALS patients without POAG did not support the contribution of OPTN in ALS [3–5]. Thus, the relationship between ALS and mutations in the OPTN gene remains controversial. We report the first case of a patient with both ALS and familial POAG without OPTN mutation. 2. Case report A 75 year-old man was first seen in October 2010 for a one-year history of progressive left lower limb weakness. His past medical history was dominated by familial POAG that involved also his father and one of his two brothers. There was no consanguinity within the family or neurological disorders.
Clinical examination showed motor weakness of grade 4 in the left leg, and grade 5 in the upper limbs. Atrophy was seen proximally in the lower limbs and in the hands. Tendon reflexes were hypoactive in the legs and brisk in the arms. Plantar responses were extensor with bilateral Hoffmann's signs. Fasciculations were profuse at the four limbs. There were no sensory, sphincter, oculomotor, cerebellar or extra pyramidal signs. The ALSFRS-R score was 42 out of 48. Nerve conduction studies were normal in all four limbs without conduction block. Electromyography disclosed denervation in four limbs, sparing the tongue. Spinal and cerebral MRI were both normal as was the spinal fluid analysis. Blood examination excluded all ALS mimicking syndromes. Riluzole was initiated in November 2010. Three months later, the ALSFRS-R score was graded 40 and clinical examination showed progression of the upper motor neuron and lower motor neuron signs. Owing to the presence of POAG in this family, the entire coding sequence of the OPTN gene and its proximal promoter was screened by bidirectional DNA sequencing analysis (ABI 3130xl; Applied Biosystems, Courtaboeuf, France) (primers available upon request). We observed no variation in the OPTN gene. We also excluded mutations in the coding sequences of SOD1, TARDBP and FUS genes. Our observation supports the weakness of the linkage between the OPTN gene and sporadic ALS. 3. Discussion
⁎ Corresponding author at: INSERM 930, Faculté de Médecine, 10, Boulevard Tonnellé, 37044 Tours CEDEX1, France. Tel.: + 33 247473724; fax: + 33 247473808. E-mail address: [email protected] (P. Corcia). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.044
Although the onset of ALS was at least 15 years later than those noted in ALS linked to OPTN gene mutations, we studied the gene for possible mutations because of association identified by other authors;
P. Corcia et al. / Journal of the Neurological Sciences 309 (2011) 16–17
OPTN mutations have been detected in familial POAG and ALS, an association that was strengthened by the discovery of a homozygous Q398X mutation in OPTN in a Japanese patient who developed ALS and POAG [1,2]. Marayuma and colleagues did not report whether the relatives of the patient who carried a heterozygous mutation Q398X in OPTN also suffered from POAG [1]. We did not detect a mutation in the entire coding sequence or the proximal promoter of the OPTN gene in our patient with ALS and familial POAG. Moreover, we were able to sequence the exon 5 of OPTN, indicating that the patient did not carry a homozygous deletion of this exon (Alu-mediated recombination) similar to the one reported by Marayuma and colleagues in two ALS patients from a single family [1]. The prevalence of mutations in the OPTN gene was estimated to be 17% in the familial POAG population [2]. Although it remains difficult to assess the frequency of OPTN mutation in ALS because of the small number of studies performed to date, it seems negligible (3/1379 sporadic ALS patients; 0.2%) [1,3,4]. Thus, mutations in the OPTN gene could be involved in a very small number of ALS cases. However, our observation, the first of a case of
17
ALS with familial POAG not showing a mutation of the OPTN gene, suggests that OPTN may not be implicated in the etiology of ALS. The co-occurrence of these two disorders, POAG and ALS, might be due to chance alone.
References [1] Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010;465:223–6. [2] Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;295:1077–9. [3] Belzil V, Daoud H, Desjarlais A, Bouchard JP, Dupré N, Camu W, et al. Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis. Neurobiol Aging 2011;32(3):555. [4] Iida A, Hosono N, Sano M, Kamei T, Oshima S, Torao Tokuda T, et al. Optineurin mutations in Japanese amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry (in press). [5] Millecamps S, Boillée S, Chabrol E, Camu W, Cazeneuve C, Salachas F, et al. Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 2011;32(3):557.